| Literature DB >> 30643281 |
Erin Nolin1, Sara Gans1, Luis Llamas1, Somnath Bandyopadhyay1, Scott M Brittain1, Paula Bernasconi-Elias1, Kyle P Carter2, Joseph J Loureiro1, Jason R Thomas1, Markus Schirle1, Yi Yang1, Ning Guo1, Guglielmo Roma3, Sven Schuierer3, Martin Beibel3, Alicia Lindeman1, Frederic Sigoillot1, Amy Chen1, Kevin X Xie1, Samuel Ho1, John Reece-Hoyes1, Wilhelm A Weihofen1, Kayla Tyskiewicz1, Dominic Hoepfner3, Richard I McDonald1, Nicolette Guthrie1, Abhishek Dogra1, Haibing Guo4, Jian Shao1, Jian Ding1, Stephen M Canham1, Geoff Boynton1, Elizabeth L George1, Zhao B Kang1, Christophe Antczak1, Jeffery A Porter1, Owen Wallace1, John A Tallarico1, Amy E Palmer2, Jeremy L Jenkins1, Rishi K Jain1, Simon M Bushell5, Christy J Fryer6.
Abstract
The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.Entities:
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Year: 2019 PMID： 30643281 PMCID： PMC7251565 DOI： 10.1038/s41589-018-0200-7
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040